Optogenetics: Manipulating Genes Through Light

FRANCES DING

For decades, geneticists have recognized DNA as the molecule that stores heritable information–the “blueprint” for life. This blueprint doesn’t stay static, though – complex mechanisms in the body are constantly turning genes on and off, regulating their expression. One of the major hurdles of genetic research has been the problem of studying these changes in real time. Now scientists at MIT and the Broad Institute have made breakthroughs in controlling genes by shining light on cells.

Their work is based in the field of optogenetics, a technique that uses proteins that change shape in the presence of light. The researchers at the Broad Institute used these light-sensitive proteins to cause genes to be either repressed or activated, with effects measurable in seconds or minutes. By contrast, chemical methods of regulating gene expression can take days. This new method has the potential to unlock many of the mysteries of learning, memory, and development, which have so far been difficult to isolate and control. In particular, this method does not require external, lab-created genes. “This method is able to target the gene in its natural state in the genome,” says Mark Brigham, a graduate student at Harvard University and one of the lead authors of the study.

In a paper published in the journal Nature in July, Brigham and MIT graduate student Silvana Konermann, along with a team of researchers, described their novel system of genetic control. First, they determined their target DNA sequences and constructed a chain of transcription activator-like effector proteins (TALEs), which can be linked together to match any genetic sequence. These TALE proteins were also attached to the light-sensitive protein Cryptochrome (CRY2) from the plant Arabidopsis thaliana. CRY2 quickly alters its shape in the presence of light and tries to bind with its partner protein CIB1, which the researchers modified to be attached to another protein that could either suppress or initiate gene transcription. The study worked with human cell lines and mice in vivo.

This new method has the potential to unlock many of the mysteries of learning, memory, and development, which have so far been difficult to isolate and control.

These components were delivered into cells with viral vectors, and the TALE proteins rapidly bound to their target DNA in a snake-like spiral, also bringing along the CRY2. Once the researchers shone light on the cells, CRY2 rapidly bound to CIB1, which was already attached to either an activator to begin the process of DNA reading and copying, or a repressor, to prevent it. The components of this system were also chosen to respond quickly when the light was turned off, giving the scientists very precise temporal control over the gene expression.

Previous research has suggested that epigenetics plays an important role in memory, learning, and development. With this kind of control, researchers can now study the specific genetic processes behind these phenomena. Epigenetics is the process in which DNA expression is altered without requiring any mutations in the underlying code. Until now, attempts to control epigenetics were unable to target specific loci. Describing the implications of this new method, Brigham says, “People are now making maps, not only of the genome, but of the epigenetic marks that go with it…. That’s kind of a readout of what happens. If you want to perturb that map and say, what happens if you make a change at a certain time point, and what causal effect does that have, that’s where our project comes in.”

The researchers did not limit themselves to one species when developing their method. “We used effector domains that come from all sorts of different species – human, mouse, plant, bacteria, plasmodium, virus, frog,” says Brigham. In the future, the team plans to explore other molecular mechanisms to switch DNA expression on and off. In the long run, this research may shine light on new answers to how the human mind develops and how the differences between humans and other species are not only genetic but also epigenetic.

Frances Ding is a Brevia staff writer. She can be reached at francesding@college.harvard.edu. Featured image credit: Allvoices